544. Pharmacokinetic Profile of Ibalizumab From a Phase 3 Trial. (26th November 2018)

• Record Type: Journal Article
• Authors: Kumar, Princy N; Weinheimer, Steven; Cohen, Zvi; Marsolais, Christian; Kuo, Kuei-Ling; Lewis, Stanley
• Is Part Of: Open forum infectious diseases. Volume 5(2018)Supplement 1
• Page Start: S202
• Page End: S202
• Publication Date: 2018-11-26
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofy210.552
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Ibalizumab (IBA) is a long-acting humanized monoclonal antibody that binds domain 2 of the CD4 receptor and blocks HIV-1 infection of host cells. TMB-301 was a 24-week, Phase 3 clinical trial conducted in 40 heavily treatment-experienced patients with multidrug-resistant (MDR) HIV-1 investigating the safety, efficacy and tolerability of IBA. Patients received a 2, 000 mg IBA loading dose followed by 800 mg every 2 weeks by intravenous infusion plus an optimized background regimen. Viral load <50 and <200 HIV RNA copies/mL was achieved in 43% and 50% of patients, respectively, at Week 25. We determined the pharmacokinetic profile of IBA, i.e., serum concentrations, CD4 receptor occupancy (RO), and CD4 receptor density (RD), in these patients with MDR HIV-1. Methods: Pre- and post-dose blood samples collected at various time points during trial were used to determine IBA serum concentrations, CD4 RO and RD at trough. IBA serum concentrations were measured using a validated ELISA. IBA bound to CD4+ T cells (RO) and cell surface CD4 levels (RD) were measured simultaneously by flow cytometry using the Molecules of Equivalent Soluble Fluorescence approach. Results: The maximum IBA serum concentrations were observed immediately after the end of the 2, 000 mg infusion with mean (SD) of 567 (235) μg/mL. Steady state was reached at Week 4 after the loading dose. The mean IBA concentrations were >30 μg/mL throughout the dosing period. Both Cpeak and Ctrough (Day 7 and Week 25 IBA concentrations) were decreased with increased body weight. The median Ctrough in the high body weight group (≥85 kg) was 0.23 μg/mL. The mean RO was >85% throughout the dosing period. The 2, 000 mg loading dose helped to reach >85% RO after the initial dose and maintain high levels of RO throughout the dosing period. Elevation in RO was generally associated with increased IBA serum concentrations; concentrations ≥0.13 μg/mL supported ≥85% CD4 RO. After IBA administration, down-modulation of surface CD4 receptors by up to 20% was observed. There was no apparent association between IBA serum concentration and RD probably due to high inter-individual variation. Conclusion: Dosing regimen of 2, 000 mg loading dose followed by 800 mg every 2 weeks was sufficient to support high levels of RO and to maintain the drug concentration above the therapeutic level. Disclosures: P. N. Kumar, TheraTechnologies: Consultant and Investigator, Consulting fee and Research grant. ViiV: Consultant, Investigator and Shareholder, Research grant and Speaker honorarium. Merck: Investigator and Shareholder, Research grant. Gilead: Consultant, Investigator and Shareholder, Consulting fee and Research grant. S. Weinheimer, TaiMed Biologics: Employee, Salary. Z. Cohen, Theratechnologies Inc.: Employee, Salary. C. Marsolais, Theratechnologies Inc.: Employee, Salary. K. L. Kuo, TaiMed Biologics Taiwan: Employee, Salary. S. Lewis, TaiMed Biologics: Employee, Salary.